The overall goal of this Program Project is to investigate determinants of atherogenic and antiatheorgenic properties of specific subpopulations of plasma lipoproteins by manipulating genes affecting lipoprotein structure, metabolism, and function in animal models. The Program Project comprises a highly interactive, multidisciplinary group of investigators and collaborators with strengths in lipoprotein biochemistry and metabolism, cell biology, lipoprotein oxidation, molecular genetics, transgenic and gene knockout techniques, and statistics. The specific aims of this Program Project proposal are organized into three complementary projects relating to the 0006 central theme. A continuing goal of Project 0006 has been to determine the origins and metabolic behavior of apoB-containing lipoprotein subclasses, particularly those associated with a human atherogenic phenotype characterized by a predominance of small, dense LDL. This goal will be addressed by testing the effects of specific genetically-induced metabolic alterations in strains of mice expressing high levels of a spectrum of LDL subclasses with properties similar to those found in humans. The studies in Project 0008 extend initial observations regarding atherogenic properties of apo(a) in transgenic mouse models by using genetic techniques to investigate specific structural determinants of this athergenicity, and related effects on targets in the artery wall. In Project 0004, the focus has been on factors responsible for HDL assembly and for the role of HDL proteins in cellular lipid removal. In the present proposal, emphasis will be shifted to the use of cellular systems and transgenic mouse models to assess the biogenesis and antiatherogenic function of HDL subpopulations transporting antioxidant enzymes. The Lipoprotein Analysis Core will provide a range of lipid, lipoprotein, and apolipoprotein measurements and contribute immunochemical expertise to each of the Projects. A second Core unit will create transgenic mice and carry out quantitative measurements of atherosclerosis. In summary, the completion of the proposed aims will advance our understanding of metabolic and structural features of specific lipoprotein subpopulations that are involved in promoting and retarding atherogenesis. This information, in turn, can have considerable impact on the ability to identify atherosclerosis susceptibility in humans, and to devise approaches that can augment the benefits of cholesterol-lowering therapy in the prevention and management of coronary artery disease.